tbuckley/cabot-search huggingface dataset:
Abstract 6787: Vaccinia virus harboring TRAIL (vTRAIL) for in vivo lung cancer therapy
Authors: So Young Yoo
Journal: Cancer Research (2023)

Abstract While oncolytic virotherapy has shown promising results for uncured patients with cancer, its effects on lung cancer remain unclear. Lung cancer is mostly unlikely to respond to conventional anticancer drug, therefore, oncolytic virotherapy can be the best option. Herein, we evaluated the anti-cancer activity of the previously developed three oncolytic vaccinia viruses encoding TNF-related apoptosis-inducing ligand (TRAIL), angiopoietin 1 (Ang1) and both genes, especially on killing lung cancer (LC). In this study, we confirmed that our engineered vaccinia viruses showed overall higher anti-cancer activity on lung cancer cells, compared to WT. Vaccinia virus engineered with both Ang1 and TRAIL (vTRAN) showed the highest oncolytic activity and selectivity in vitro (WT &amp;lt; vTRAIL &amp;lt; vAng1 &amp;lt; vTRAN). However, In vivo LLC1 murine lung cancer syngeneic model showed highest attenuated tumor growth when vTRAIL was treated (WT &amp;lt; vAng1 &amp;lt; vTRAN &amp;lt; vTRAIL), which was in accordance with CD8 high PD1 low expression levels in the tissues. It concludes that engineered vaccinia virus harboring TRAIL (vTRAIL) is the promising therapeutic option for in vivo lung cancer therapy. Citation Format: So Young Yoo. Vaccinia virus harboring TRAIL (vTRAIL) for in vivo lung cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6787.
Abstract 5345: The application of CDK16 inhibitors in the treatment of triple-negative breast cancer
Authors: Haihua Xiao, Huangyu Jiang, Kunxian Feng, Mengli Yang, Jinping Yang, Chengfang Jian, Yuan Tian, Natalya Vasilevich, Lichun Sun
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) with estrogen receptor (ER), progesterone receptor (PR) and HER2 (c-erbB-2, neu) being negatively expressed in patient cancer tissues displayed its unique clinical pathological difference from other types of breast cancers. TNBC is more common in younger patients and more likely to have a family history of breast cancer. TNBCs more likely have poor prognosis and postsurgical recurrence, with strong invasiveness and metastasis. However, there is lack of effective and TNBC-targeting drugs. The non-typical CDK16 was found highly expressed in TNBCs and clearly associated with prognosis and survival of patients. CDK16 could promote the progression and metastasis of TNBC by phosphorylating PRC1. Knockdown of CDK16 could significantly suppress tumor growth and metastasis. Furthermore, in our studies, rebastinib acting as a CDK16 inhibitor displayed its strong suppression of TNBC tumor growth in a dose-dependent manner, indicating rebastinib or its analogs could be druggable and likely used to treat TNBC patients. Citation Format: Haihua Xiao, Huangyu Jiang, Kunxian Feng, Mengli Yang, Jinping Yang, Chengfang Jian, Yuan Tian, Natalya Vasilevich, Lichun Sun. The application of CDK16 inhibitors in the treatment of triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5345.
Abstract 1495: Developing a model to investigate the roles of biomolecular condensates in papillary renal cell carcinoma
Authors: Choon Leng So, Jane Lee, Binglin Huang, Danfeng Cai
Journal: Cancer Research (2023)

Abstract Cells are compartmentalized into “classical” membrane-bound organelles such as the endoplasmic reticulum and mitochondria. Cells also have membrane-less organelles (MLOs), which are formed through phase separation. Examples of MLOs include stress granules and nucleoli, where macromolecules (proteins, DNAs, RNAs) coherently and dynamically concentrate into biomolecular condensates resembling droplets in lava lamps. MLOs play central role in cellular processes - choreographed events such as transcription and RNA splicing take place in MLOs. MLOs are highly organized, and their dysregulation always led to diseases. Papillary renal cell carcinoma (PRCC) is the second most common RCC in America. PRCC is an aggressive cancer, yet the uncharacterized molecular etiology results in the lack of effective treatment for patients. Our lab and others have observed dysregulated oncoproteins MLOs in PRCC. However, the molecular properties and functions of these aberrant MLOs have not been characterized. The photolyase homology region of Arabidopsis thaliana Cry2 (Cry2WT) is a light-sensitive protein that self-associate with blue light exposure. We hypothesize that fusing dysregulated MLOs oncoproteins with Cry2WT will allow us to tune and study the oncoproteins condensates. We aim to develop an optogenetic model to study how oncoproteins condensates function in PRCC cells. Dysregulated oncoproteins were fused to mCherry-Cry2WT, introduced into cell line models, light-activated and imaged using a ZEISS LSM 900 microscope. We found that blue-light indeed induced proteins clustering when oncoproteins were fused to mCherry-Cry2WT but not with mCherry-Cry2WT alone. This model will allow us to tune the formation of oncoproteins condensates. Future work will involve studying how optogenetically tuned oncoproteins condensates function in PRCC patient-derived cell lines. Citation Format: Choon Leng So, Jane Lee, Binglin Huang, Danfeng Cai. Developing a model to investigate the roles of biomolecular condensates in papillary renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1495.
Abstract 6070: Comprehensive real-world-data based molecular profiling and mapping of non-squamous NSCLC patients to immune-checkpoint-inhibitor biomarkers
Authors: Andreas Kloetgen, Danyi Wang, Anna Coenen-Stass, Ioannis Gounaris, Julia F. Hopkins, Giuseppe Locatelli, Juergen Scheuenpflug, Zheng Feng
Journal: Cancer Research (2023)

Abstract Purpose: Non-squamous non-small cell lung cancer (nsqNSCLC) patients without detectable actionable alterations in EGFR, ALK, or ROS1, have a diverse genetic background. These patients are eligible to and usually receive untargeted, first line immune checkpoint inhibitors (ICI) and/or chemotherapy with heterogeneous outcomes. To identify potential predictive biomarkers for the stratification of nsqNSCLC patients without actionable genetic alterations, a comprehensive molecular profiling of this subpopulation was performed using the Foundation Medicine genomic database. Methods: Molecular profiles from 53,119 nsqNSCLC patients were analyzed using the FoundationInsightsTM web platform. After the patients with known and likely functional short variants for EGFR and fusions for ALK and ROS1 were excluded, the prevalences for commonly altered genes were determined. Pathway analysis was conducted with Metascape. Statistical significance and enrichment in PD-L1 and tumor mutation burden (TMB) biomarker overlap with altered genes was calculated using a fisher exact test against an alteration negative cohort. Results: nsqNSCLC patients without actionable genetic alterations can be described as a heterogenous population with different genetic alterations. We found a total of 103 genes with an individual, minimal prevalence of &amp;gt;1% to be the major descriptors that collectively were found in most patients of the nsqNSCLC subpopulation. These genes relate to pathways involved in cell cycle, cell proliferation, response to growth factors or chromatin organization. Out of the most frequently altered genes, we identified those that are associated with PD-L1 or TMB high status for which ICI treatment is most effective in nsqNSCLC. Conclusions: The results supported the lack of a general association with high PD-L1 and high TMB calls for biomarker informed treatment options for nsqNSCLC patients. We reported a subpopulation of nsqNSCLC patients that can be described by certain genetic alteration, of which some were associated with ICI-related biomarkers for which patients might benefit from a future precision oncology approach utilizing combined targeted and ICI treatment. Citation Format: Andreas Kloetgen, Danyi Wang, Anna Coenen-Stass, Ioannis Gounaris, Julia F. Hopkins, Giuseppe Locatelli, Juergen Scheuenpflug, Zheng Feng. Comprehensive real-world-data based molecular profiling and mapping of non-squamous NSCLC patients to immune-checkpoint-inhibitor biomarkers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6070.
Abstract 3842: Berberine recognition of the dGMP-bound PDGFR-β promoter G-quadruplex: Structural insight into specific drug targeting
Authors: Kai-Bo Wang, Jonathan Dickerhoff, Yichen Han, Danzhou Yang
Journal: Cancer Research (2023)

Abstract PDGFR-β (Platelet-Derived Growth Factor Receptor beta) is a receptor tyrosine kinase whose overexpression drives the progression and metastasis of many cancers. It is an established anticancer target and PDGFR-β inhibition via kinase inhibitors has been actively sought-after. However, PDGFR-β kinase inhibitors often lack specificity. The PDGFR-β gene promoter forms DNA G-quadruplexes that are transcription silencer whose stabilization by small molecules represses PDGFR-β expression. Therefore, targeting PDGFR-β promoter G-quadruplexes for transcriptional silencing is a promising alternative strategy for cancer therapy. G-quadruplex is an exciting family of non-canonical DNA secondary structures. DNA G-quadruplex within the PDGFR-β gene promoter forms novel vacancy pockets (vG4) that can be filled-in by guanine metabolites such as dGMP and cGMP. This presents an attractive target for small molecule targeting. Herein, we present the binding of the natural product berberine with the unique PDGFR-β dGMP-vG4 binary complex to form a novel ternary complex, the first case observed in DNA G-quadruplexes. Using circular dichroism, fluorescence, and nuclear magnetic resonance (NMR) spectroscopy, we demonstrated that berberine binds with high affinity and strongly stabilizes the dGMP-fill-in PDGFR-β vG4. Our determined high-resolution NMR structure of this ternary complex in K+-containing solution reveals a 2:1 binding stoichiometry of berberine to the dGMP-fill-in PDGFR-β vG4. Significantly, one berberine directly stacks upon and extensively covers the dGMP. This direct binding mode provides structural basis for targeting the unique PDGFR-β promoter G-quadruplex by small molecules and suggests an intriguing strategy of designing drug-like, guanine-conjugated molecules to selectively silence the PDGFR-β gene. Because vG4 formation and dGMP fill-in is a unique property of the PDGFR-β promoter G-quadruplex, our study provides a structural basis for rationally designing small molecule drugs to specifically target the PDGFR-β promoter G-quadruplex to inhibit oncogenic PDGFR-β for cancer therapeutics. Citation Format: Kai-Bo Wang, Jonathan Dickerhoff, Yichen Han, Danzhou Yang. Berberine recognition of the dGMP-bound PDGFR-β promoter G-quadruplex: Structural insight into specific drug targeting. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3842.
Abstract 1989: DNA-encoded affinity maturation libraries enable the discovery of low picomolar fibroblast activation protein inhibitors suitable for radioligand therapy of solid tumors
Authors: Sara Puglioli, Luca Prati, Sebastian Oehler, Andrea Galbiati, Dario Neri, Samuele Cazzamalli, Gabriele Bassi, Nicholas Favalli
Journal: Cancer Research (2023)

Abstract The discovery of potent ligands highly specific to accessible cancer-associated antigens is essential for the development of small molecule therapeutics with broad therapeutic index. DNA-encoded chemical libraries (DELs) can be used to discover novel binders and to improve binding affinity of existing small organic ligands by affinity maturation procedures. OncoFAP is a 680 pM inhibitor of the stromal pan-tumoral antigen Fibroblast Activation Protein (FAP). OncoFAP displays best-in-class tumor targeting performance in patients, although its relatively short half-life limits the applicability as radioligand therapeutic against solid malignancies. We designed three focused affinity maturation DELs, containing 50,730 compounds bearing two sets of building blocks coupled to a propargylglycine central scaffold. Library selections against FAP from multiple species enabled the discovery of novel FAP inhibitors with potencies in the low picomolar range. 177Lu-DOTAGA conjugates of the most potent novel ligands (named “OncoFAP-11” and “BiOncoFAP-11”) localized to tumors implanted in mice, with excellent tumor-to-blood and tumor-to-kidney ratios at late time-points after systemic administration. The high affinity FAP ligands described here enable the efficient delivery of therapeutic radionuclides to tumors with long residence time and with low uptake in normal tissues. The results presented here show that DEL-based affinity maturation procedures can lead to the improvement of the targeting performance of FAP binders, without compromising their tumor selectivity. Citation Format: Sara Puglioli, Luca Prati, Sebastian Oehler, Andrea Galbiati, Dario Neri, Samuele Cazzamalli, Gabriele Bassi, Nicholas Favalli. DNA-encoded affinity maturation libraries enable the discovery of low picomolar fibroblast activation protein inhibitors suitable for radioligand therapy of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1989.
Abstract 2403: Divergent evolutionary response to multiple fractions of radiation (MF2) therapy in cervical cancer cell lines (CCCL)
Authors: Johanna Kelley, Arda Durmaz, Michelle Kuznicki, Aaron Petty, Jacob Scott, Roberto Vargas
Journal: Cancer Research (2023)

Abstract Introduction: Treatment for locally-advanced cervical cancer is not currently tailored based on genomic markers of treatment response. We aim to explore the potential for differential evolutionary trajectories of radiation (RT) resistance throughout treatment using two in vitro models. Methods: Sixteen cervical cancer cell lines ( CCCL) were exposed to 1.8 Gy fractions of RT radiation for five sequential days and the surviving fraction (MF2) calculated. Differential gene expression (DGE) was performed on pre and post - treatment samples. Partial least squares (PLS) regression was completed with MF2 as the endpoint . Protein-protein interaction (PPI) network and overrepresentation analysis of genes was also performed. Four CCCL (BOKU, SKG II SF, ME180, and HeLa) were serially exposed to 50 Gy of gamma radiation RT given in 2Gy fractions. Five evolutionary replicates and three passage-controls were maintained. The mean integral survival as a function of dose (AUC) was calculated and ANOVA analysis performed. Results: MF2 as the phenotypic endpoint identified 19 DE genes. PLS identified histones (H4C8, H2BC18, H2BC4) as positively associated and transcriptional regulators (NR2F1, KALRN) as negatively associated with MF2 (Figure 1AB). PPI and Reactome Pathways also highlighted histone deacetylase pathways, nucleosome assembly and regulation of membrane potentials (Figure 1BC). Longitudinal treatment RT identified differential evolutionary trajectories between CCCL replicates. Two BOKU (p = 0.005 and 0.0090), one SKG II SF (p = 0.0146), and one ME180 (p = 0.0384) replicates became resistant. Four SKG II SF (p &amp;lt; 0.0001), and two HeLa (p = 0.0005 and p = 0.0068) became more sensitive to radiationRT (1C). Conclusion: Divergent evolutionary trajectories under therapeutic stress can be elicited using in vitro evolutionary experimentation with cervical cancer cell linesCCCL. Genomic correlation with divergent evolutionary trajectories may allow for the identification of real-time markers of resistance or sensitivity and allow for true RT radiotherapy personalization. Citation Format: Johanna Kelley, Arda Durmaz, Michelle Kuznicki, Aaron Petty, Jacob Scott, Roberto Vargas. Divergent evolutionary response to multiple fractions of radiation (MF2) therapy in cervical cancer cell lines (CCCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2403.
Abstract 4929: ICX-101, a novel MYC inhibitor, shows antitumor activity in patient-derived cells of advanced lung cancer with high MYC expression
Authors: Wonyoung Choi, Kyung-Chae Jeong, Seog-Yun Park, Sunshin Kim, Eun Hye Kang, Mihwa Hwang, Ji-Youn Han
Journal: Cancer Research (2023)

Abstract Background: MYC is an attractive therapeutic target in lung cancer. ICX-101 is a novel potent, selective small molecule that directly inhibits the binding of MYC/MAX dimers to the DNA binding sequence E-box. Here, we show that ICX-101 shows antitumor activity in patient-derived cells (PDC) of advanced lung cancer and that the drug responses are correlated with the MYC expression levels. Methods: PDCs of lung cancer were treated with ICX-101, and the area under the dose-response curve (AUC) was measured as the readout for antitumor efficacy. MYC expression level of each PDC was measured with the fold expression of mRNA compared to the normal lung tissue. The patient’s clinical data and survival outcomes were analyzed to correlate with the drug responses of PDCs. Results: We collected 100 PDCs from 82 lung cancer patients. The histologic types included adenocarcinoma (N = 82), squamous cell carcinoma (N = 10), non-small cell lung cancer (NSCLC) not otherwise specified (NOS) (N = 4), and small cell lung cancer (SCLC, N = 4). PDCs derived from SCLC showed higher MYC expression levels than NSCLC (P = 0.004). MYC was a prognostic factor, as the patient groups with the top and bottom 25 percentiles of MYC mRNA expression had an overall survival of 932.5 and 256 days, respectively (P = 0.029). However, MYC expression was predictive for the response to ICX-101, as the PDCs with the top 25 percentiles of MYC levels showed markedly lower AUC values than those with the bottom 25 percentile (P &amp;lt; 0.001). Additionally, the MYC mRNA levels and AUC values were inversely correlated with statistical significance (R = -0.46, P &amp;lt; 0.001). Conclusion: ICX-101 is a potent MYC inhibitor that shows antitumor activity in lung cancer PDCs. Our results suggest the potential of ICX-101 as a possible therapeutic option in advanced lung cancer with high MYC expressions. Citation Format: Wonyoung Choi, Kyung-Chae Jeong, Seog-Yun Park, Sunshin Kim, Eun Hye Kang, Mihwa Hwang, Ji-Youn Han. ICX-101, a novel MYC inhibitor, shows antitumor activity in patient-derived cells of advanced lung cancer with high MYC expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4929.
Abstract 6073: Distinct subtype of multiple myeloma revealed by whole genome and transcriptome sequencing
Authors: Sheehyun Kim, Hyundong Yoon, Youngil Koh, Sung-Soo Yoon
Journal: Cancer Research (2023)

Abstract Background: Advanced sequencing technologies have contributed to identifying genomic and transcriptomic features of various types of tumors. Despite several sequencing data from multiple myeloma (MM) being generated, understanding various properties of MM remained insufficient. Methods: The patients confirmed with MM by bone marrow examination were analyzed in the study. Myeloma cells were enriched from the bone marrow aspirates of the patients using CD138. Whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) were performed for isolated myeloma cells. Mutational signatures were analyzed using somatic mutations detected by WGS. Results: A total of 37 MM patients (median age 67) were enrolled in this study. WGS revealed somatic mutations of an average of 8872 single nucleotide variants (SNVs) and 934 insertions and deletions (Indels) from the patients, respectively. By the analysis of structural variants, 7 chromothripsis and 4 chromoplexy patients were identified. Mutational signature analysis showed that single base substitution (SBS) 9 signature largely varied between patients. SBS9 signature high patients were mostly diagnosed with non-IgG/non-IgA heavy chain and lambda light chain type myeloma. Notably, IgD myeloma patients were solely detected in the SBS9 signature high group compared to the low group (p = 0.001). Gene expression patterns obtained from WTS were well-divided into SBS9 signature high and low groups, and analysis of differentially expressed genes (DEG) between SBS9 signature high and low groups implied IgD myeloma features including high expression of IGHD. As a validation test, we tried mutational signature analysis on whole exome sequencing (WES) data of 784 MM patients from the MMRF database. Of the 38 patients with more than 500 exonic mutations, only the SBS9 signature high group had IgD myeloma candidates, whereas the SBS9 signature low group had no IgD myeloma candidate (p = 0.014). Conclusions: DNA and RNA sequencing of myeloma patients could classify specific subtypes of disease categories. Further study for SBS 9 signature high and IgD myeloma is needed to discover the underlying mechanism of distinct features and to find out their clinical implication. Citation Format: Sheehyun Kim, Hyundong Yoon, Youngil Koh, Sung-Soo Yoon. Distinct subtype of multiple myeloma revealed by whole genome and transcriptome sequencing. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6073.